The antiproliferative and differentiation-inducing effects of all-trans retinoic acid (RA) and sodium butyrate (SB) were investigated in four pancreatic ductal adenocarcinoma cell lines, two poorly differentiated ones (PT45 and PaTu-II), one moderately to poorly differentiated one (Panc-1) and one highly differentiated one (A818-1). Treatment with 20 microM RA resulted in moderate inhibition of cell growth in all cell lines, but clear evidence of cytodifferentiation (including elongated cell processes, increased rough endoplasmic reticulum, intensified immunostaining for the mucin marker (M1) was found only in PT45 and Panc-1. These phenotypic changes were paralleled by upregulation of RAR (retinoic acid receptor)-alpha and -gamma mRNA. SB (1 and 2 mM) treatment inhibited the cell growth of all cell lines much more prominently than RA. Cytodifferentiation was also largely restricted to PT45 and Panc-1. A noticeable phenomenon was enhancement of the expression of the neuroendocrine markers synaptophysin and Lcu7 in Panc-1 cells. In conclusion, it is evident that the original differentiation status of cells and their responsiveness to the agents are not clearly associated, and that RA responsiveness correlates with upregulation of RAR-alpha and -gamma mRNA.
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